Desquamation/epidermal renewal of the skin and/or combating skin aging

ABSTRACT

Cinnamic acid and derivatives thereof are well suited for promoting desquamation and/or stimulating epidermal renewal and/or combating intrinsic/extrinsic aging of the skin of a human subject in need of such treatment, by topically applying thereto, for such period of time as required to elicit the desired response, a cosmetically/therapeutically effective amount of cinnamic acid and/or of at least one derivative thereof.

CROSS-REFERENCE TO RELATED AND PRIORITY APPLICATIONS

[0001] This application is a continuation of copending U.S. applicationSer. No. 09/305,213, filed May 5, 1999, now allowed, incorporated byreference herein in its entirety and relied upon, which claims priorityunder 35 U.S.C. §119 of FR-98/05967, filed May 12, 1998, expresslyincorporated by reference therein.

BACKGROUND OF THE INVENTION

[0002] 1. Technical Field of the Invention

[0003] The present invention relates to promoting desquamation of theskin and/or stimulating epidermal renewal and/or combating aging of theskin by topical application thereto of cinnamic acid or derivativethereof, or composition comprising same.

[0004] The compounds/compositions of this invention are especially wellsuited for promoting desquamation of the skin and/or stimulatingepidermal renewal and/or combating intrinsic and/or extrinsic aging ofthe skin, as well as for nontherapeutically treating the skin to promotedesquamation and/or combat aging of the skin.

[0005] 2. Description of the Prior Art

[0006] Desquamation is a natural phenomenon associated with the factthat the epidermis, which constitutes the upper layer of the skin, is inconstant regeneration. The epidermis consists of several layers ofcells, the deepest of which is the basal layer consisting ofundifferentiated cells. These cells differentiate and migrate towardsthe surface of the epidermis over time, constituting the various layersthereof, until they form at the surface of the epidermis thecorneocytes, which are dead cells, which are removed by desquamation.This loss of surface is compensated for by the migration of cells fromthe basal layer towards the surface of the epidermis. This entailsperpetual renewal of the skin. Forced removal of the horny layeraccelerates the renewal and makes it possible to combat aging.

[0007] At the same time, these cells continue their differentiation, thefinal stage of which is the corneocyte. These are dead cells which makeup the final layer of the epidermis, namely, the outermost layer alsoknown as the stratum corneum.

[0008] Aging of the skin resulting from the effects of intrinsic orextrinsic factors on the skin is reflected by the appearance of wrinklesand fine lines, by yellowing of the skin which develops a parchment-likeappearance accompanied by the appearance of pigmentation blemishes, bythe disorganization of the elastin and collagen fibers, causing a lossof elasticity, flexibility and firmness, and by the appearance oftelangiectases.

[0009] Certain of these signs of aging are more particularly associatedwith intrinsic or physiological aging, namely, with “normal” aging dueto age or chronobiological aging, whereas others are more specific toextrinsic aging, namely, aging caused in general by the environment;this relates more particularly to photoaging due to exposure tosunlight, to light or to any other radiation, whether natural orartificial.

[0010] The present invention relates to not only intrinsic orphysiological aging, but also to extrinsic aging.

[0011] The changes in the skin due to intrinsic aging are theconsequence of a genetically programmed senescence involving endogenousfactors. This intrinsic aging causes, in particular, a slowing down orretarding of the renewal of the skin cells, which is reflectedessentially by the appearance of clinical impairments such as reductionin the subcutaneous adipose tissue and the appearance of small wrinklesor fine lines, and by histopathological changes such as an increase inthe number and thickness of elastic fibers, a loss of vertical fibersfrom the membrane of the elastic tissue, and the presence of largeirregular fibroblasts in the cells of this elastic tissue.

[0012] By contrast, extrinsic aging causes clinical impairments such aslarge wrinkles and the formation of a flaccid and weathered skin, andhistopathological changes such as excessive accumulation of elasticmaterial in the epidermis and degeneration of the collagen fibers.

[0013] Various active agents suggested for combating aging of the skinare known in the prior art.

[0014] Thus, U.S. Pat. No. 4,603,146 describes the use of retinoic acidand derivatives thereof in cosmetic compositions for combating skinaging.

[0015] Moreover, many patents and publications (see, for example,EP-A-413,528) describe, and numerous commercially available commercialcosmetic compositions include, α-hydroxy acids, such as lactic acid,glycolic acid or citric acid, for treating aging of the skin.

[0016] Too, the β-hydroxy acids, and more especially salicylic acid andderivatives thereof, are known for their desquamating properties (seeWO-A-93/10756 and U.S. Pat. No. 4,767,750).

[0017] All of the aforesaid prior art compounds elicit action againstaging of the skin by promoting desquamation, i.e., the removal of the“dead” cells located at the surface of the horny layer of the epidermis.This “desquamating” property is also referred to, often incorrectly, asa keratolytic property.

[0018] However, the compounds of the prior art also presentobjectionable side effects, such as stinging, tautness and sensations ofoverheating and redness which are unpleasant for the user.

[0019] Need therefore continues to exist for antiaging agents having anaction which is at least as effective as that of the compounds of theprior art, but which do not present the disadvantages thereof.

SUMMARY OF THE INVENTION

[0020] Accordingly, a major object of the present invention is theprovision of active agents for promoting desquamation of the skin and/orfor stimulating epidermal renewal, while at the same time avoiding thestinging, tautness or sensations of overheating or redness which areunpleasant for the user and which to date have characterized the stateof this art.

[0021] Briefly, it has now surprisingly and unexpectedly been determinedthat topically applying an effective amount of cinnamic acid or of atleast one derivative thereof onto the skin promotes the desquamationthereof and/or stimulates epidermal renewal and therefore combats skinaging.

[0022] Thus, this invention features formulating an effective amount ofcinnamic acid or at least one derivative thereof intocosmetic/therapeutic compositions that promote desquamation of the skinand/or stimulate epidermal renewal and/or combat intrinsic and/orextrinsic aging of the skin.

[0023] The present invention also features a non-therapeuticregime/regimen for treating the skin to promote desquamation thereofand/or to stimulate epidermal renewal and/or to combat intrinsic and/orextrinsic aging of the skin.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

[0024] More particularly according to the present invention, it will beappreciated that cinnamic acid is present in trans-form in the essentialoils of basil and of cinnamon, in Peruvian balsamine and in cacaoleaves. The cis-form is present in the oil from Alpinia malacensis.

[0025] In the prior art, cinnamic acid or derivatives thereof have beenformulated into compositions for preventing bedsores (JP-07,242,558), asanti-ultraviolet active agents (U.S. Pat. No. 5,093,109), inpermanent-waving compositions (DE-3,301,515, DE-2,912,477 andEP-22,996), in hair lotions (JP-7,053,401 and JP-3,041,413), indepigmenting compositions (JP-5,221,845 and JP-1,186,811) and asantioxidants (EP-664,290).

[0026] However, to date the use of cinnamic acid or derivative thereoffor promoting desquamation of the skin and/or stimulating epidermalrenewal and/or combating intrinsic and/or extrinsic aging of the skinwas unknown.

[0027] The present invention therefore features the use of an effectiveamount of cinnamic acid or of at least one derivative thereof, orcomposition comprised thereof, to promote desquamation of the skinand/or to stimulate epidermal renewal and/or to combat intrinsic and/orextrinsic aging of the skin.

[0028] The cinnamic acid or derivative thereof can be of natural orsynthetic origin. By the term “natural origin” is intended cinnamic acidor derivative thereof prepared from plant material in which they existin the natural state. By the term “synthetic origin” is intendedcinnamic acid or derivative thereof, prepared via chemical synthesis orbiotechnology.

[0029] Thus, the term “cinnamic acid” connotes cinnamic acid orderivative thereof, of natural or synthetic origin, in purified form, orin any preparation comprising same.

[0030] Exemplary cinnamic acid derivatives according to the invention,include, for example, mono- and polyhydroxycinnamic acids, alcohols,aldehydes, esters and derivatives thereof.

[0031] Cinnamic acid is the preferred compound according to theinvention.

[0032] Too, the cinnamic acid or derivative thereof can be used eitheralone or in any admixture of same.

[0033] The amount of cinnamic acid or derivative thereof which can beused according to the invention obviously depends on the desired effectand should be an amount which is effective for promoting desquamation ofthe skin and/or stimulating epidermal renewal and/or combating intrinsicand/or extrinsic aging of the skin.

[0034] For example, the amount of cinnamic acid or of at least onederivative thereof according to the invention advantageously ranges, forexample, from 10⁻⁶% to 10% and preferably from 10⁻³% to 5% of the totalweight of the composition.

[0035] This invention also features compositions for promotingdesquamation of the skin and/or stimulating epidermal renewal and/orcombating intrinsic and/or extrinsic aging of the skin, comprising aneffective amount of at least cinnamic acid or at least one derivativethereof, formulated into appropriate cosmetically/dermatologicallyacceptable medium therefor (diluent, vehicle or carrier).

[0036] In the compositions of the invention, the cinnamic acid or atleast one derivative thereof can be present in an amount ranging from10⁻⁶% to 10% and preferably from 10⁻³% to 5% of the total weight of thecomposition.

[0037] This invention also features a nontherapeutic regime/regimen forpromoting desquamation of the skin and/or stimulating epidermal renewaland/or combating intrinsic and/or extrinsic aging of the skin,comprising topically applying a cosmetic composition containing aneffective amount of cinnamic acid or derivative thereof onto the skin.

[0038] The subject compositions can be formulated into any knownpharmaceutical form such as, for example, as an emulsion, in particularan oil-in-water or water-in-oil emulsion, or even in the form of amultiple emulsion.

[0039] They may also be provided in the form of an aqueous solution,which may be gelled, or in the form of a lotion, for example a two-phaselotion, an ointment, a cream, a milk or a mousse (foam).

[0040] The compositions according to this invention may comprise an oilyphase based on animal, plant, mineral, silicone, fluoro and/or syntheticoil.

[0041] The oily phase may also comprise fatty alcohols or fatty acids,as well as surfactants.

[0042] Exemplary are the hydrocarbon-based oils such as liquid paraffinor liquid petroleum jelly; perhydrosqualene; arara oil, sweet almondoil, beauty-leaf oil, palm oil, castor oil, avocado oil, jojoba oil,olive oil or cereal germ oil; alcohols such as oleyl alcohol, linoleylalcohol, linolenyl alcohol, isostearyl alcohol or octyldodecanol. Alsoexemplary are the silicone oils such as PDMSs, optionally phenylated,such as phenyltrimethicones.

[0043] The oily phase may also comprise a makeup-removing oil such as afatty acid ester, in particular the esters obtained from a straight- orbranched-chain alcohol having from 1 to 17 carbon atoms and from astraight- or branched-chain fatty acid having from 3 to 18 carbon atoms.

[0044] Representative such esters include dioctyl adipate, 2-ethylhexylpalmitate, diisopropyl adipate, 2-ethylhexyl hexanoate, ethyl laurate,methyl myristate, octyldodecyl octanoate, isodecyl neopentanoate, ethylmyristate, myristyl propionate, 2-ethylhexyl 2-ethylhexanoate,2-ethylhexyl octanoate, 2-ethylhexyl caprate/caprylate, methylpalmitate, butyl myristate, isobutyl myristate, ethyl palmitate,isohexyl laurate, hexyl laurate and isopropyl isostearate.

[0045] The oily phase advantageously constitutes from 5%-95% by weightin the case of an emulsion.

[0046] The compositions according to the invention may also comprise, inaddition:

[0047] (i) an agent permitting the fatty phase to be placed insuspension, for example a copolymer of C₁₀-C₃₀ alkyl acrylates and ofacrylic or methacrylic acid or ester thereof(Pemulen TR1, Pemulen TR2and Carbopol 1342 marketed by Goodrich); or anacrylamide/methylpropanesulfonic acid copolymer (Sepigel marketed bySEPPIC), and/or

[0048] (ii) an agent for dispersing the fatty phase, such as anemulsifying or vesicular system based on vesicles, optionally ofnanometric size, comprising ionic lipids (liposomes) or nonionic lipids,and in particular the emulsifying systems which are well known to theart, and comprising glyceryl stearate/PEG 100 stearate (CTFA), cetylalcohol and stearyl alcohol.

[0049] The compositions of the invention too may comprise an agent formodifying its viscosity, and for providing more or less gelled textures,such as:

[0050] (iii) cellulose derivatives (carboxymethylcellulose,hydroxyethylcellulose or hydroxypropylmethylcellulose),

[0051] (iv) natural gums such as xanthan gum, guar gum or carob gum,scleroglucans, chitin or chitosan derivatives, and carrageenans,

[0052] (v) polycarboxyvinyl derivatives such as Carbomer (marketed byGoodrich under the trademarks Carbopol 940, 951 and 980, or by 3V-Sigmaunder the trademark Synthalen K or Synthalen L).

[0053] The compositions according to the invention may also compriseconventional additives and adjuvants for cosmetic/dermatologicalapplications, such as preservatives, antioxidants, fragrances, fillerssuch as kaolin or starch, or even hollow microspheres, pigments, UVscreening agents, sequestering agents, essential oils, dyestuffs,colorants, odor absorbers, hydrophilic or lipophilic active agents suchas moisturizers, in particular glycerol or butylene glycol,anti-inflammatory agents such as allantoin and bisabolol,anti-free-radical agents such as alantoin or bisabolol,anti-free-radical agents such as vitamin E or derivative thereof,soothing agents such as cornflower water or extract of iris,depigmenting agents, biological active agents such as urea, amino acids,vitamins and derivative thereof, proteins, salicylic acid andderivatives thereof, α-hydroxy acids, pyrrolidonecarboxylic acid and itssalts, and ceramides.

[0054] One skilled in this art will of course take care to select thisor these optional complementary compounds, and/or the amount thereof,such that the advantageous properties of the compositions according tothe invention are not, or are not substantially, adversely affected bythe addition envisaged.

[0055] The subject compositions preferably have a pH which does notdamage the skin, generally ranging from 5 to 8, preferably a pH of from5.5 to 7.5.

[0056] The compositions of the invention are well suited for cosmetic orpharmaceutical use, particularly dermatological use.

[0057] The subject compositions are typically formulated for topicalapplication/administration.

[0058] In order to further illustrate the present invention and theadvantages thereof, the following specific examples are given, it beingunderstood that same are intended only as illustrative and in nowiselimitative.

EXAMPLE 1

[0059] The capacity of cinnamic acid to promote desquamation of the skinwas examined:

[0060] This test of in vitro screening of an active agent ondesquamation was carried out on differentiated human keratinocytes. Theprinciple of the test was based on the fact that desquamation inducesthe release of corneocytes. The desquamating power of the product testedwill be proportionately greater the larger the number of corneocytesreleased.

[0061] The test procedure was as follows: starting with human skinbiopsies, the keratinocytes obtained by separation of the epidermis weredissociated by enzymatic action with trypsin and were cultured at aconcentration of 2×10⁵ cells/ml. Growth and differentiation of thekeratinocytes were obtained by culturing for 10 to 20 days in a specificmedium. Next, after removing the culture medium, the activity of thetest product was evaluated. To do this, two samples were taken at T0 andT60, i.e., just before adding the product and 60 minutes after thisaddition. The samples thus taken were analyzed with a flow cytometer inorder to count the corneocyte population. The flow cytometer made itpossible to distinguish the corneocyte and keratinocyte populations bytreatment with acridine orange, which is specific for cellular DNA. Thisstaining was specific for the keratinocytes since normal corneocytes donot contain a nucleus and thus no DNA.

[0062] The cellular detachment index was determined by the differencebetween T60 and T0. The same measurement was carried out for a controlcontaining no test product, since the experimental conditions inevitablyinduced the release of corneocytes, even in the absence of activeagents.

[0063] The test was carried out with cinnamic acid at a concentration of5×10⁻⁵M.

[0064] The results of these studies are reported in the Table below:TABLE Compounds at 5 × 10⁻⁵M % p** Reference* 96.6 <0.05 Cinnamic acid59.2 >0.05 Control 0 —

[0065] The results are given as a % of activity relative to the controlconsisting of an identical culture in the absence of compound.

[0066] The activity of the cinnamic acid on the cellular detachment,thus, was high.

EXAMPLE 2

[0067] Examples of specific formulations according to the invention;these compositions were formulated by simple intimate admixing of thevarious components: Composition 1: Facial milk Liquid petroleum jelly7.0 g Cinnamic acid 2.0 g Glyceryl monostearate, polyethylene glycolstearate 3.0 g (100 EO) Carboxyvinyl polymer 0.4 g Stearyl alcohol 0.7 gSoybean proteins 3.0 g NaOH 0.4 g Preservative qs Water qs 100 g

[0068] This composition was in the form of a facial milk having goodcosmetic properties and was mild and comfortable to use.

[0069] The pH of the composition was about 5.5. Composition 2: LotionCinnamic acid  0.5 g 2-Ethylhexyl palmitate 10.0 gCyclopentadimethylsiloxane 20.0 g Butylene glycol  5.0 g Preservative qsWater qs 100 g

[0070] This lotion, which contained no surfactant, promoted desquamationof the skin. Composition 3: Milk Octyl palmitate 35.0 g Glycerol  2.0 gCinnamic acid  2.0 g C10-C30 acrylates/alkylacrylates  0.1 g crosslinkedpolymer Triethanolamine  0.1 g Amino acids from wheat  1.0 gPreservative qs Water qs 100 g

[0071] The milk obtained, which contained no surfactant, had goodcosmetic properties. Composition 4: Facial gel Glycerol 10.0 g Cinnamicacid  1.0 g Disodium cocoamphodiacetate  1.0 g Preservative qs Water qs100 g

[0072] The gel obtained had good cosmetic properties. Composition 5:Cleansing gel with water Butylene glycol 7.0 g Sodium lauroylsarcosinate 4.0 g Cinnamic acid 0.5 g Triethanolamine 0.8 g Carbomer 0.5g Preservatives qs Water qs 100 g

[0073] The gel obtained had good cosmetic properties.

[0074] While the invention has been described in terms of variouspreferred embodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

What is claimed is:
 1. A method for promoting desquamation orstimulating epidermal renewal of the skin of a human subject in need ofsuch treatment, comprising topically applying thereto a cosmetic ordermatological composition comprising a desquamation-effective orepidermal renewal-effective amount of a cinnamic acid ester, formulatedinto a topically applicable, cosmetically or dermatologically acceptablevehicle, diluent or carrier therefor, said cinnamic acid ester being thesole active agent for promoting desquamation or stimulating epidermalrenewal in said composition.
 2. A method for promoting desquamation ofthe skin of a human subject in need of such treatment, comprisingtopically applying thereto a cosmetic or dermatological compositioncomprising a desquamation-effective amount of a cinnamic acid ester,formulated into a topically applicable, cosmetically or dermatologicallyacceptable vehicle, diluent or carrier therefor, said cinnamic acidester being the sole active agent for promoting desquamation in saidcomposition.
 3. A method for stimulating renewal of the epidermal skinof a human subject in need of such treatment, comprising topicallyapplying thereto a cosmetic or dermatological composition comprising anepidermal renewal-effective amount of a cinnamic acid ester, formulatedinto a topically applicable, cosmetically or dermatologically acceptablevehicle, diluent or carrier therefor, said cinnamic acid ester being thesole active agent for stimulating epidermal renewal in said composition.4. The method as defined by claim 1, wherein said composition includesonly ingredients or amounts thereof which do not cause the side-effectsensations of stinging, tautness, overheating or redness of the skin. 5.The method defined by claim 2, wherein said composition includes onlyingredients or amounts thereof which do not cause the side-effectsensations of stinging, tautness, overheating or redness of the skin. 6.The method as defined by claim 3, wherein said composition includes onlyingredients or amounts thereof which do not cause the side-effectsensations of stinging, tautness, overheating or redness of the skin. 7.The method as defined by claim 1, wherein the amount of cinnamic acidester present in the composition ranges from 10⁻⁶% to 10% by weight ofthe total weight.
 8. The method as defined by claim 2, wherein theamount of cinnamic acid ester present in the composition ranges from10⁻⁶% to 10% by weight of the total weight.
 9. The method as defined byclaim 3, wherein the amount of cinnamic acid ester present in thecomposition ranges from 10⁻⁶% to 10% by weight of the total weight. 10.The method as defined by claim 7, wherein the amount of cinnamic acidester present in the composition ranges from 10⁻³% to 5% by weight ofthe total weight.
 11. The method as defined by claim 8, wherein theamount of cinnamic acid ester present in the composition ranges from10⁻³% to 5% by weight of the total weight.
 12. The method as defined byclaim 9, wherein the amount of cinnamic acid ester present in thecomposition ranges from 10⁻³% to 5% by weight of the total weight. 13.The method as defined by claim 1, wherein said composition has a pHranging from 5 to
 8. 14. The method as defined by claim 2, wherein saidcomposition has a pH ranging from 5 to
 8. 15. The method as defined byclaim 3, wherein said composition has a pH ranging from 5 to 8.